The nature of autoantigens responsible for autoimmune disorders is not known, nor is the action which triggers the autoimmune response. One theory involves the similarity of a viral protein to a self antigen, which results in autoreactive T cells or B cells recognizing a self antigen. Whereas B-lymphocytes produce antibodies, thymus-derived or “T-cells” are associated with cell-mediated immune functions. T-cells recognize antigens presented on the surface of cells and carry out their functions with these “antigen-presenting” cells.
Various markers have been used to define human T cell populations. CD4 is a non-polymorphic surface glycoprotein receptor with partial sequence identity to immunoglobulins. CD4 receptors define distinct subsets of mature peripheral T cells. In general, CD4 T cells express helper or regulatory functions with B cells in immune responses, while T cells express the CD8 surface antigen function as cytotoxic T cells and have suppressive effects in immune responses. The CD4 receptor consists of a signal peptide, a 370 amino acid extracellular region containing four tandem immunoglobulin-like domains (V1–V4), a membrane spanning domain, and a charged, intracellular region of forty (40) residues.
Since T-cell receptors are thought to augment or modulate T-cell response, they present a potential target for immunological intervention. One approach to the treatment of autoimmune disorders involves monoclonal antibodies specific for CD4 receptors. Murine anti-CD4 monoclonal antibodies appear useful in the treatment of rheumatoid arthritis as disclosed in Hertzog, C. et al. Lancet, page 1461 (Dec. 19, 1987). Murine antibodies, however, have characteristics which may severely limit their use in human therapy. As foreign proteins, murine antibodies may elicit immune reactions that reduce or destroy their therapeutic efficacy and/or evoke allergic or hyper-sensitivity reaction in patients. The need for readministration of such therapeutic modalities in autoimmune disorders increases the likelihood of these types of immune reactions.
Chimeric antibodies consisting of non-human antigen binding regions joined to human constant regions have been suggested as a means to circumvent the immunogenicity of murine antibodies. See e.g. PNAS, 81:6851 (1984) and PCT Application No. PCT/GB85 00392. Since the constant region is largely responsible for immunogenicity of an antibody molecule, chimeric antibodies with constant regions of human origin should be less likely to evoke an anti-murine response in humans. However, it is unpredictable whether the joining of a human constant region to a nonhuman antigen binding region of a desired specificity will reduce immunoreactivity and/or alter the binding capabilities or the biological activity of the resulting chimeric antibody. Furthermore, immunoglobulin constant regions exist as a variety of isotypes, which are responsible for different effector functions. Therefore the biological activity of a chimeric antibody will depend on the isotype of the constant regions as well as the nature of the antigen-binding regions.
Not all anti-CD4 monoclonal antibodies bind to the same CD4 site or domain, and the site to which a particular monoclonal antibody binds may significantly affect its biological activity, e.g., its immunomodulatory activity, or its ability to block the binding of HIV to CD4 cells, for example.